Much of what is known about the genetic basis of basal cell carcinoma (BCC) derives from studies of patients with Gorlin syndrome, an autosomal dominant disorder caused by germline mutations in the PTCH gene. Among other features, Gorlin syndrome patients develop numerous BCCs and are predisposed to developing other types of tumors. In addition, up to 60% of sporadic BCCs harbor mutations in PTCH or SMO, a target of PTCH suppression, and about 50% show loss of heterozygosity (LOH) for the PTCH locus at chromosome 9q22.3. We hypothesize, however, that genetic aberrations in addition to or instead of PTCH or SMO gene defects may contribute to BCC tumorigenesis, given that a significant proportion of sporadic BCCs carry neither PTCH nor SMO gene defects. Furthermore, other BCC susceptibility disorders, such as nonsyndromic hereditary multiple basal cell carcinoma (NSHMBCC), are phenotypically distinct from Gorlin syndrome and may be caused by mutations in a gene other than PTCH. We propose to identify novel genes involved in the pathogenesis of sporadic BCCs and NSHMBCC. In preliminary studies, we have used array based comparative genomic hybridization (CGH) to identify regions of chromosomal loss in sporadic BCCs. We observed deletion of the PTCHlocus in 8/24 BCC samples and losses at 6 other loci in over 20% BCCs studied. We propose to extend these studies by performing array-based CGH on additional tumor samples to narrowly define alternative loci consistently deleted in sporadic BCC (aim 1). We will then screen candidate genes in such regions for inactivating mutations to identify putative tumor suppressor genes. Similarly, we propose to identify the underlying gene defect in patients with NSHMBCC (aim 2). We hypothesize that these subjects harbor a mutation in a tumor suppressor gene that predisposes to development of BCCs. LOH through deletion of the remaining allele, would then be permissive for BCC tumorigenesis. We propose to perform array-based CGH to define a consistently deleted chromosomal region in tumors from NSHMBCC subjects. We will then assess candidate genes within such a region for germline mutations in NSHMBCC patients. Therefore, by using array-based CGH as a method for detecting and mapping chromosomal aberrations, we anticipate identifying putative tumor suppressor genes that may represent novel components of the PTCH/SHH signaling pathway and contribute to the pathogenesis BCC and potentially other tumor types as well.